Filed: February 28, 2017

Filed on behalf of: Otsuka Pharmaceutical Co., Ltd.

UNITED STATES PATENT AND TRADEMARK OFFICE ___________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

___________

ALKERMES PHARMA IRELAND LTD. and ALKERMES, INC.,

Petitioner,

v.

OTSUKA PHARMACEUTICAL CO., LTD., Patent Owner.

____________________________________________

Case IPR2017-00287 Patent 9,125,939 B2

____________________________________________

PATENT OWNER’S PRELIMINARY RESPONSE

U.S. Patent No. 9,125,939 IPR2017-00287

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TABLE OF CONTENTS

Page(s)

I. Introduction ...................................................................................................... 1

II. Petitioner Has Not Established That Keck, Citrome & BMS/Otsuka Press Release Are Printed Publications As Required by § 311(b) .................. 3

A. An IPR Challenge Can Only Rely on Printed Publications .................. 4

B. Petitioner Provides No Evidence of the Publication, Dissemination, or Public Availability of Keck and Citrome ................ 6

1. Dr. Frances’s Testimony Fails to Establish that Keck and Citrome Were Published ............................................................. 6

2. Petitioner Did Not Provide the Source of Keck and Citrome ......................................................................................10

C. Petitioner Provides No Evidence of the Publication, Dissemination, or Public Availability of BMS/Otsuka Press Release .................................................................................................10

1. Petitioner Provides No Evidence Supporting the Publication of BMS/Otsuka Press Release Before the Critical Date ..............................................................................11

2. Petitioner Fails to Establish That Persons Interested in the Art Would Have Been Able to Access BMS/Otsuka Press Release .............................................................................14

3. Petitioner Does Not Provide the Source of BMS/Otsuka Press Release .............................................................................15

III. Even If Certain Documents Constitute Printed Publications, Which Petitioner Has Not Shown, Petitioner Fails to Establish a Reasonable Likelihood that Any Claim is Unpatentable ..................................................16

A. Petitioner Fails to Establish the Requisite Motivation to Support Its Proposed Grounds of Unpatentability ............................................17

U.S. Patent No. 9,125,939 IPR2017-00287

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1. Petitioner Has Not Demonstrated That Atypical Antipsychotics Would Be Added to Mood Stabilizers “Whenever the Mood Stabilizer Was Insufficiently Effective” ..................................................................................17

2. Petitioner Does Not Argue and Provides No Evidence that Aripiprazole Was Viewed as Interchangeable With Other Atypical Antipsychotics for Bipolar Disorder ................21

3. Petitioner’s Remaining Documents Do Not Cure These Deficiencies ...............................................................................23

B. Petitioner Provides No Basis to Support a Reasonable Expectation of Success ........................................................................25

1. Petitioner Does Not Account for Aripiprazole’s Distinctiveness ..........................................................................26

2. Petitioner Does Not Account for the Claimed Patient Population .................................................................................28

3. Petitioner’s Allegation of Reasonable Expectation of Success Impermissibly Relies on the ’939 Patent Specification ..............................................................................32

IV. Petitioner’s Grounds Should Be Denied as Redundant to the Art and Arguments Previously Considered and Overcome During Prosecution .......33

A. The Board Should Deny Institution Where the Same or Substantially the Same Prior Art or Arguments Were Previously Presented ...........................................................................33

B. Summary of the Prosecution of the ’939 Patent .................................34

C. Petitioner Relies on the Same or Cumulative Documents and Uses Them in the Same Way the Examiner Did .................................39

1. Keck and BMS/Otsuka Press Release are Cumulative of Clinical Trial Report .................................................................39

2. Tohen is Tohen ..........................................................................40

U.S. Patent No. 9,125,939 IPR2017-00287

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3. Citrome is Almost Citrome S187 ..............................................41

4. APA Guidelines are Cumulative of Kowatch ...........................43

5. Expert Consensus Adds Nothing to the Art the Examiner Considered ................................................................................46

6. Conclusion ................................................................................48

D. Petitioner’s “Side Effects” Arguments Are Irrelevant ........................49

E. Petitioner’s Arguments Regarding Dr. Hirose’s Declaration Are Irrelevant and Do Not Undermine the Examiner’s Conclusions Regarding Patentability .......................................................................50

1. The Hirose Data ........................................................................50

2. The Results Do Not Change by Expressing Them as % Suppression or by Normalizing Them ......................................53

3. The Data was Sufficiently Explained .......................................54

4. Dr. Au’s Synergy Model Would Not Have Been Appropriate ...............................................................................57

5. Dr. Au’s Arguments Strongly Suggest that a Person of Ordinary Skill in the Art Would Not Have Had a Reasonable Expectation of Success ..........................................57

V. Petitioner’s Six Grounds of Unpatentability Are Redundant of One Another ..........................................................................................................59

A. All Grounds Are Horizontally Redundant ..........................................59

B. Grounds 1 and 4, Grounds 2 and 4, and Grounds 2 and 6 Are Vertically Redundant ...........................................................................61

VI. Conclusion .....................................................................................................63

U.S. Patent No. 9,125,939 IPR2017-00287

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TABLE OF AUTHORITIES

Page(s)

Cases

Air Liquide Large Indus. U.S., LP v. Praxair Tech. Inc., IPR2015-01074, Paper 11 (P.T.A.B. Oct. 26, 2015) .......................................... 13

Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009) .......................................................................... 25

Apotex Inc. v. OSI Pharms., Inc., IPR2016-01284, Paper 8 (P.T.A.B. Jan. 9, 2017) .............................................. 33

Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281 (Fed. Cir. 1985) ............................................................................ 18

Boehringer Ingelheim Int’l GmbH v. Biogen Inc., IPR2015-00418, Paper 14 (P.T.A.B. July 13, 2015) ...................................passim

Broadcom Corp. v. Emulex Corp., 732 F.3d 1325 (Fed. Cir. 2013) .......................................................................... 25

Cisco Sys., Inc. v. Constellation Techs. L.L.C., IPR2014-01085, Paper 11 (P.T.A.B. Jan. 9, 2015) ............................................ 15

Coal. for Affordable Drugs IV LLC (“ADROCA”) v. Pharmacyclics, Inc., IPR2015-01076, Paper 33 (P.T.A.B. Oct. 19, 2015) ...................................passim

Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346 (Fed. Cir. 2010) .......................................................................... 49

DePuy Spine, Inc v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 28

DIRECTV, LLC v. Qurio Holdings, Inc., IPR2015-02006, Paper 6 (P.T.A.B. Apr. 4, 2016) ....................................... 18, 19

EMC Corp. v. PersonalWeb Techs., LLC, IPR2013-00082, Paper 33 (P.T.A.B. June 5, 2013) ........................................... 60

U.S. Patent No. 9,125,939 IPR2017-00287

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Ford Motor Co. v. Versata Dev. Grp., Inc., IPR2016-01012, Paper 12 (P.T.A.B. Nov. 4, 2016) ....................................passim

Gen. Elec. Co. v. TAS Energy Inc., IPR2014-00163, Paper 11 (P.T.A.B. May 13, 2014) ................................... 18, 23

Google Inc. v. ART+COM Innovationpool GmbH, IPR2015-00789, Paper 8 (P.T.A.B. Sept. 2, 2015)........................................ 4, 13

Groupon, Inc. v. Blue Calypso, LLC, CBM2013-00035, Paper 45 (P.T.A.B. Dec. 17, 2014) ........................................ 5

In re Bayer, 568 F.2d 1357 (Fed. Cir. 1978) .......................................................................... 14

In re Cronyn, 890 F.2d 1158 (Fed. Cir. 1989) ............................................................................ 4

In re Klopfenstein, 380 F.3d 1345 (Fed. Cir. 2004) ............................................................................ 7

In re Lister, 583 F.3d 1307 (Fed. Cir. 2009) ............................................................................ 5

In re Magnum Oil Tools Int’l., Ltd., 829 F.3d 1364 (Fed. Cir. 2016) .......................................................................... 23

Intelgenx Corp v. ICOS Corp., IPR2016-00678, Paper 13 (P.T.A.B. Sept. 1, 2016)........................................... 31

Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359 (Fed. Cir. 2016) .................................................................... 26, 29

Jiawei Tech. (HK) Ltd. v. Richmond, IPR2014-00937, Paper 22 (P.T.A.B. Dec. 16, 2014) ......................................... 31

Kayak Software Corp. v. Int’l Bus. Machs. Corp., CBM2016-00075, Paper 16 (P.T.A.B. Dec. 15, 2016)...................................... 34

KSR Int’l v. Teleflex Inc., 550 U.S. 398 (2007) ...................................................................................... 28, 32

U.S. Patent No. 9,125,939 IPR2017-00287

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LG Elecs., Inc. v. Advanced Micro Devices, Inc., IPR2015-00329, Paper 13 (P.T.A.B. July 10, 2015) .......................................... 11

Liberty Mutual Ins. Co. v. Progressive Casualty Ins. Co., CBM2012-00003, Paper 7 (P.T.A.B. Oct. 25, 2012) ................................... 59, 61

Life Techs. v. Clontech Labs., Inc., 224 F.3d 1320 (Fed. Cir. 2000) .......................................................................... 32

Logic Tech. Dev., LLC v. Fontem Holdings 1 B.V., IPR2015-00098, Paper 8 (P.T.A.B. May 11, 2015) ........................................... 23

Lower Drug Prices for Consumers, LLC v. Forest Labs. Holdings Ltd., IPR2016-00379, Paper 14 (P.T.A.B. July 1, 2016) ............................................ 33

Microsoft Corp. v. Corel Software, LLC, IPR2016-01300, Paper 13 (P.T.A.B. Jan. 4, 2017) ............................................ 14

Mylan Pharms. Inc. v. Yeda Research & Dev. Co., PGR2016-00010, Paper 9 (P.T.A.B. Aug. 15, 2016) ......................................... 33

Neil Ziegmann, N.P.Z., Inc. v. Stephens, IPR2015-01860, Paper 11 (P.T.A.B. Feb. 24, 2016) .......................................... 33

Norian Corp. v. Stryker Corp. 363 F.3d 1321 (Fed. Cir. 2004) ............................................................................ 8

Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 3:07-cv-01000, 2010 WL 4596324 (D.N.J. Nov. 15, 2010) .............................. 22

Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. 2012) .......................................................................... 22

Par Pharm. Inc. v. Jazz Pharm. Ireland Ltd., IPR2016-00002, Paper 12 (P.T.A.B. Apr. 12, 2016) ......................................... 27

Personal Web Techs., LLC v. Apple, Inc., --- F.3d ----, 2017 WL 587132 (Fed. Cir. Feb. 14, 2017) ................................... 20

Phigenix, Inc. v. Genentech, Inc., IPR2014-00842, Paper 10 (P.T.A.B. Dec. 9, 2014) ........................................... 30

U.S. Patent No. 9,125,939 IPR2017-00287

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Praxair Distribution, Inc. v. INO Therapeutics, Inc., IPR2015-00522, Paper 12 (P.T.A.B. July 29, 2015) .............................. 13, 18, 23

PRISM Pharma Co. v. Choongwae Pharma Corp., IPR2014-00315, Paper 14 (P.T.A.B. July 8, 2014) ............................................ 34

ResQNet.com, Inc. v. Lansa, Inc., 594 F.3d 860 (Fed. Cir. 2010) ...................................................................... 15, 42

SAS Institute, Inc. v. ComplementSoft, LLC, IPR2013-00581, Paper 17 (P.T.A.B. Feb. 25, 2014) .......................................... 23

Square, Inc. v. Unwired Planet, LLC, CBM2014-00156, Paper 11 (P.T.A.B. Dec. 24, 2014) ...................................... 11

SRI Intern., Inc. v. Internet Sec. Sys., Inc., 511 F.3d 1186 (Fed. Cir. 2008) ...................................................................... 5, 15

Star Sci., Inc. v. R.J. Reynolds Tobacco Co., 655 F.3d 1364 (Fed. Cir. 2011) .......................................................................... 20

Temporal Power, Ltd. v. Beacon Power, LLC, IPR2015-00146, Paper 10 (P.T.A.B. Apr. 27, 2015) ......................................... 10

Whole Space Indus. Ltd. v. Zipshade Indus. (B.V.I.) Corp., IPR2015-00488, Paper 14 (P.T.A.B. July 24, 2015) .......................................... 18

Federal Statutes

35 U.S.C. § 102(b) ......................................................................................... 7, 11, 14

35 U.S.C. § 103(a) ................................................................................................... 32

35 U.S.C. § 311(b) ............................................................................................passim

35 U.S.C. § 325(d) ............................................................................................passim

35 U.S.C. § 371 ........................................................................................................ 34

Regulations

37 C.F.R. § 42.107 ..................................................................................................... 1

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Other Authorities

H.R. REP. No. 112-98, pt.1 (2011) ........................................................................... 33

U.S. Patent No. 9,125,939 IPR2017-00287

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PATENT OWNER’S EXHIBIT LIST

EXHIBIT DESCRIPTION

2001

Image of webpage accessed via hyperlink, http://www.prnewswire.com/news-releases/data-demonstrate-aripiprazole-significantly-improved-symptoms-of-acute-mania-in-patients-with-bipolar-disorder-77570072.html, provided by Dr. Frances in Ex. 1002, ¶ 35

2002 Burris et al., Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D2 Receptors, 302 J. PHARMACOLOGY & EXPERIMENTAL THERAPEUTICS 381 (2002)

2003 Jordan et al., U.S. Patent Application Publication No. 2002/0173513

2004 Clinical Trial Report, CN138-00ST (“Clinical Trial Report”)

2005 Citrome et al., Pharmacokinetics and Safety of Aripiprazole and Concomitant Mood Stabilizers, 5 INT’L J. NEUROPSYCHOPHARMACOLOGY, S187, P.4.E. 035

2006 November 15, 2002, Prescription Information of Abilify®

2007 November 15, 2002, Letter from the FDA regarding Approval of Abilify®

2008 Excerpt from Hirose Declaration, Ex. 1076 at 1162

U.S. Patent No. 9,125,939 IPR2017-00287

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I. Introduction

Patent Owner Otsuka Pharmaceutical Co., Ltd. respectfully submits this

preliminary response under 37 C.F.R. § 42.107 to the Petition for Inter Partes

Review of U.S. Patent No. 9,125,939 (“the ’939 patent”).

The claims relate to a method of treating bipolar disorder in a patient

partially nonresponsive to lithium or valproic acid, divalproex sodium or a salt

thereof monotherapy by administering aripiprazole and lithium in a ratio of about 1

part by weight aripiprazole to about 0.01 to 500 parts by weight lithium. Petitioner

contends that claims 2, 6, 7, and 9 would have been obvious according to six

proposed grounds of unpatentability. The requested grounds, however, fail to

demonstrate that trial should be instituted for three independent reasons.

First, negating all six grounds, Petitioner fails to establish that at least three

of the documents that it relies on are printed publications as required by § 311(b).

Specifically, Petitioner does not establish that the abstracts of Keck (Ex. 1007) and

Citrome (Ex. 1008) were publicly available at any date before the ’939 patent was

filed, let alone as of the critical date. Petitioner also fails to provide sufficient

evidence to establish that Otsuka/BMS Press Release (Ex. 1028) was publicly

available before the critical date or that it would have been accessible to the

interested public.

U.S. Patent No. 9,125,939 IPR2017-00287

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Second, even if Petitioner’s documents constitute printed publications,

which Petitioner has not shown, none of its requested grounds establishes a

reasonable likelihood that any challenged claim is unpatentable. Every ground

relies on the same conclusions that preliminary findings for specific atypical

antipsychotics would have been extrapolated to all atypical antipsychotics,

including aripiprazole, and that aripiprazole would have been expected to have the

same usefulness in combination with mood stabilizing drugs as other antipsychotic

medication. The record, however, does not support these conclusions. Instead,

Petitioner’s own exhibits repeatedly recognize aripiprazole as a novel antipsychotic

having a chemical structure and mechanism of action that differed from the

marketed typical and atypical antipsychotics at the time.

Moreover, Petitioner and its declarant present no evidence to support why a

combination of aripiprazole and lithium would have been reasonably expected to

treat bipolar disorder in the specific claimed population of bipolar disorder

patients, i.e., “in a patient partially nonresponsive to lithium or valproic acid,

divalproex sodium or salt thereof monotherapy.” Petitioner instead simply

references certain examples in the ’939 patent specification and alleges that the

inventors had a reasonable expectation of success based on the prior art.

Petitioner’s reasoning is prohibited by law. It cannot rely on the examples in the

U.S. Patent No. 9,125,939 IPR2017-00287

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’939 patent or the inventors’ alleged mindset to evidence what a person of ordinary

skill in the art would have known or expected.

Third, Petitioner’s grounds simply rehash the arguments that the Office fully

vetted and ultimately withdrew during the prosecution of the ’939 patent.

Although Petitioner relies on facially different documents, the disclosures and

arguments based on them mirror the Examiner’s efforts. And none of Petitioner’s

challenges to Patent Owner’s showing of unexpected results should undo the

careful analysis that this Office already did. As a result, the Board should use its

discretion under § 325(d) to deny institution.

Thus, for these and other reasons presented below, Petitioner fails to show a

reasonable likelihood of prevailing on any challenged claim. The Board should

therefore deny institution of inter partes review.

II. Petitioner Has Not Established That Keck, Citrome & BMS/Otsuka Press Release Are Printed Publications As Required by § 311(b)

Petitioner asserts that Keck (Ex. 1007), Citrome (Ex. 1008) and

BMS/Otsuka Press Release (Ex. 1028) are prior art (Pet. at 15 n.1, 16, 22 n.2), but

fails to establish that any of those exhibits are printed publications as required by

35 U.S.C. § 311(b). The critical date of the ’939 patent is May 23, 2002, which

Petitioner does not challenge. Petitioner alleges that Keck and Citrome are

abstracts from a 2002 Annual Meeting of the American Psychiatric Association

U.S. Patent No. 9,125,939 IPR2017-00287

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(“APA”) held during May 18-23, 2002. Id. at 15 n.1, 22 n.2. Petitioner also

asserts that they were published on or before the first day of the conference, i.e.,

before the May 23, 2002, critical date. Id. Petitioner also argues that BMS/Otsuka

Press Release was published on May 22, 2002, one day before the critical date. Id.

at 16. Despite Petitioner’s assertions, however, it has not presented evidence

sufficient to establish that Keck, BMS/Otsuka Press Release, and Citrome are

printed publications at any date relevant for prior art purposes, let alone as of the

critical date. Thus, because all of Petitioner’s grounds of unpatentability rely on

either Keck or BMS/Otsuka Press Release or Citrome, the Petition must be denied

as to all grounds.

A. An IPR Challenge Can Only Rely on Printed Publications

An IPR may only be initiated “on the basis of prior art consisting of patents

or printed publications.” 35 U.S.C. § 311(b). Whether a document qualifies as a

printed publication involves a case-by-case inquiry into the facts and

circumstances surrounding the document’s disclosure to members of the public. In

re Cronyn, 890 F.2d 1158, 1161 (Fed. Cir. 1989); Google Inc. v. ART+COM

Innovationpool GmbH, IPR2015-00789, Paper 8 at 4, 6-10 (P.T.A.B. Sept. 2,

2015). The key inquiry is whether the document was made “sufficiently accessible

to the public interested in the art” before the critical date. Cronyn, 890 F.2d at

1160.

U.S. Patent No. 9,125,939 IPR2017-00287

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Petitioner has the burden of proving that a document was published or

otherwise sufficiently disseminated to the public. See, e.g., In re Lister, 583 F.3d

1307, 1317 (Fed. Cir. 2009) (burden is on the proponent to show document was

publicly available); Coal. for Affordable Drugs IV LLC (“ADROCA”) v.

Pharmacyclics, Inc., IPR2015-01076, Paper 33 at 6 (P.T.A.B. Oct. 19, 2015)

(“Petitioner must make a threshold showing that the reference is a prior art ‘printed

publication[].’”); Ford Motor Co. v. Versata Dev. Grp., Inc., IPR2016-01012,

Paper 12 at 6 (P.T.A.B. Nov. 4, 2016). A document is publicly accessible “upon a

satisfactory showing that such document has been disseminated or otherwise made

available to the extent that persons interested and ordinarily skilled in the subject

matter or art exercising reasonable diligence, can locate it.” SRI Intern., Inc. v.

Internet Sec. Sys., Inc., 511 F.3d 1186, 1195 (Fed. Cir. 2008). A conclusory

assertion without evidence of distribution or dissemination is insufficient to

establish that a document is a “printed publication.” ADROCA, IPR2015-01076,

Paper 33 at 7 (“Given his unsupported assertions, we give little to no weight to Dr.

Atanackovic’s conclusory testimony that NCT00849654 constitutes prior art.’”);

Groupon, Inc. v. Blue Calypso, LLC, CBM2013-00035, Paper 45 at 18-23

(P.T.A.B. Dec. 17, 2014).

U.S. Patent No. 9,125,939 IPR2017-00287

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B. Petitioner Provides No Evidence of the Publication, Dissemination, or Public Availability of Keck and Citrome

Petitioner fails to show that Keck and Citrome qualify as prior art printed

publications. Petitioner offers no evidence of the publication, dissemination, or

public availability to support its assertion that Keck and Citrome were published

and distributed before the critical date of the ’939 patent.

1. Dr. Frances’s Testimony Fails to Establish that Keck and Citrome Were Published

The exhibits themselves provide no support that they were published before

the critical date. Both Keck and Citrome are two-page exhibits that include an

identical first page stating “New Research Abstracts” for the 2002 Annual Meeting

of the APA. Ex. 1007 at 1; Ex. 1008 at 1. The second page of Keck indicates that

it is the eighty-sixth page of an unidentified document. Ex. 1007 at 2. Similarly,

the second page of Citrome indicates that it is the eighty-seventh page of an

unidentified document. Ex. 1008 at 2. The only dates found on either of these

documents relate to when the 2002 Annual Meeting and presentations supposedly

occurred. Ex. 1007; Ex. 1008. Accordingly, the exhibits themselves fail to

provide any indication of when they were published or disseminated to the

interested public.

Nevertheless, Petitioner asserts that Keck and Citrome are printed

publications that were available at least as early as May 18, 2002, making them

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prior art under § 102(b).1 Pet. at 15 n.1, 22 n.2. As support, Petitioner cites to Dr.

Frances’s declaration, which states that he has purportedly attended more than 20

Annual Meetings of the APA, and that Abstracts from those meetings are routinely

made available in print form to psychiatrists and to the public on or before the first

day of the conference. Id.; Ex. 1002 ¶ 34 n.3, ¶ 37 n.4. Dr. Frances did not testify

that he actually attended the 2002 Annual Meeting or that Keck and Citrome, in

particular, were actually distributed to the attendees on or before the first day of the

conference. As such, Dr. Frances fails to establish that these exhibits qualify as

prior art printed publications. To conclude otherwise would contravene Federal

Circuit and Board precedent.

Indeed, the Federal Circuit and Board both require evidence that a document

was actually published or distributed, rather than an unsupported assertion that it

1 To the extent Petitioner is arguing that the presentations themselves make Keck

and Citrome printed publications, Petitioner is wrong. An IPR may only be

initiated “on the basis of prior art consisting of patents or printed publications.” 35

U.S.C. § 311(b). Moreover, a presentation at a conference is not necessarily prior

art. In re Klopfenstein, 380 F.3d 1345, 1349 n.4 (Fed. Cir. 2004). Here, Petitioner

provides no evidence that the presentations underlying the abstracts actually

occurred.

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was. For example, in Norian Corp. v. Stryker Corp., the Federal Circuit upheld the

district court’s finding that an abstract allegedly distributed at a conference was not

a printed publication because, among other things, the co-author of the abstract

testified that he had attended the meeting and had taken along a copy of the

abstract to be given to a meeting organizer, but could not recall whether he

attended the presentation and could not recall whether copies of the abstract were

actually available to hand out. 363 F.3d 1321, 1330 (Fed. Cir. 2004). The Court

upheld this finding despite record testimony that presenters at the conference

generally provided handouts to attendees. Id. By contrast, here Petitioner provides

no evidence 1) regarding the APA’s practice of distributing conference abstracts;

2) whether the APA even had standard distribution practices; and 3) whether those

practices (which have not been shown to exist) were actually followed for the 2002

Annual Meeting. Thus, Dr. Frances’s unsubstantiated testimony that the abstracts

for the annual meetings are “routinely made available” is insufficient to establish

Keck and Citrome as printed publications. Ex. 1002 ¶ 35.

The Board also requires firsthand knowledge of a document’s alleged

dissemination to the public. For example, the petitioner in Ford argued that an

article was published during a conference. IPR2016-01012, Paper 12 at 4-5. The

Board, however, found that “the only information on the face of Stahl to indicate

that it was publicly accessible before the critical date is the header,” and that “the

U.S. Patent No. 9,125,939 IPR2017-00287

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exhibit contains no copyright date, and there is no further indication in Stahl itself

as to when and under what circumstances or conditions it may have been

disseminated to members of the public.” Id. at 7. The Board was also

unpersuaded by the expert’s testimony that the article was allegedly published

during the conference because the expert made no showing that he attended or had

personal knowledge of the conference. Id. at 8-9.

The Board has similarly held that a petitioner failed to establish that clinical

trial protocols were printed publications when petitioner’s expert testified only that

clinical trial protocols were “typically” widely disseminated, without any firsthand

knowledge about the distribution of the protocols at issue. Boehringer Ingelheim

Int’l GmbH v. Biogen Inc., IPR2015-00418, Paper 14 at 10-12 (P.T.A.B. July 13,

2015); see also, ADROCA, IPR2015-01076, Paper 33 at 7 (“Dr. Atanackovic has

not attested to any personal knowledge of the public accessibility or dissemination

of NCT00849654 in February 2009.”).

The situation is no different here. Dr. Frances claims no firsthand

knowledge of the 2002 Annual Meeting, or of the Keck and Citrome abstracts

themselves. Nor does he provide any support for the APA’s allegedly standard

distribution practice beyond a generalization from allegedly attending more than

20 annual meetings. Dr. Frances could have attempted to provide specifics,

including entries from his calendar, registration packets, and abstracts from other

U.S. Patent No. 9,125,939 IPR2017-00287

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meetings he attended to support his contention. He did not. Thus, just like the

petitioners in Ford and Boehringer, Petitioner here has failed to provide evidence

that Keck and Citrome were actually published or disseminated prior to the critical

date (or by any relevant prior art date).

2. Petitioner Did Not Provide the Source of Keck and Citrome

Moreover, Petitioner does not provide any information about where it

obtained Keck and Citrome or how Petitioner assembled those exhibits. Dr.

Frances did not testify that the exhibits were true and accurate copies of the

abstracts obtained from attending the 2002 Annual Meeting. See Ex. 1002 ¶ 34

n.3, ¶ 37 n.4. In a similar situation, where the petitioner failed to explain whether

the document at issue was an actual copy obtained at a conference, the Board

found that the petitioner failed to establish that the document qualified as a prior

art printed publication. Temporal Power, Ltd. v. Beacon Power, LLC, IPR2015-

00146, Paper 10 at 11 (P.T.A.B. Apr. 27, 2015).

Thus, for at least these reasons, Petitioner has not established that Keck and

Citrome are prior art printed publications.

C. Petitioner Provides No Evidence of the Publication, Dissemination, or Public Availability of BMS/Otsuka Press Release

Petitioner argues—without any citations to record evidence, including Dr.

Frances’s declaration—that BMS/Otsuka Press Release from PR Newswire (Ex.

U.S. Patent No. 9,125,939 IPR2017-00287

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1028) is a press release that was “available to the public at least as early as May

22, 2002,” making it § 102(b) prior art. Pet. at 16. Such an unsupported statement,

here again, cannot support a finding that BMS/Otsuka Press Release is a prior art

printed publication.

1. Petitioner Provides No Evidence Supporting the Publication of BMS/Otsuka Press Release Before the Critical Date

The Board requires petitioners to explain the nature of any alleged

publication date, and has held against them when they failed to do so. See, e.g.,

ADROCA, IPR2015-01076, Paper 33 at 7; LG Elecs., Inc. v. Advanced Micro

Devices, Inc., IPR2015-00329, Paper 13 at 13 (P.T.A.B. July 10, 2015) (“Petitioner

offers no evidence of the nature of this date.”); Square, Inc. v. Unwired Planet,

LLC, CBM2014-00156, Paper 11 at 18 (P.T.A.B. Dec. 24, 2014) (“Petitioner has

failed to provide any evidence that would allow us to determine the significance of

the ISBN number[,]” which included the alleged publication date.). For example,

in ADROCA, petitioner and its expert asserted, without evidence, that a copy of a

webpage that indicated that it was “updated” on a certain date was a printed

publication. IPR2015-01076, Paper 33 at 7. The Board held, however, that the

petitioner failed to establish the document at issue was a prior art printed

publication because the petitioner provided “no explanation or evidence of what

U.S. Patent No. 9,125,939 IPR2017-00287

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that [‘update’] date means” and offered no “evidence of the website’s publishing

practices.” Id.

Here, the facts are analogous. Ex. 1028 has three dates: (1) May 22, 2002,

in the header of the document; (2) a 2002 copyright date in the header of the

document; and (3) May 23, 2002, indicated as a “Load-Date” on the fourth page of

the document, none of which is specified as a publication date. Petitioner makes

no attempt to explain what each date means, and provides no evidence relating to

the publishing practices of PR Newswire.

Moreover, Petitioner provides no support whatsoever to establish the source,

publication, dissemination, or public availability of Ex. 1028. See Pet. at 16.

While Dr. Frances provides a hyperlink (Ex. 1002 ¶ 35), Petitioner did not

incorporate that link into the Petition. See id. Indeed, Petitioner does not even cite

to Dr. Frances’s declaration to support that Ex. 1028 is a printed publication. See

id. The Board has previously refrained from considering information that was

presented only in an expert declaration. Boehringer, IPR2015-00418, Paper 14 at

10 (The Board “decline[d] to import the extensive discussion about the public

accessibility of the ECOG protocols from Dr. Grossbard’s Declaration into the

Petition, based solely on the Petition’s citation of certain paragraphs within the

Declaration.”). Thus, the Board should not consider the hyperlink.

U.S. Patent No. 9,125,939 IPR2017-00287

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Even if it did, however, it would find that the link leads to a document that is

different from Ex. 1028. Compare Ex. 2001 with Ex. 1028. For example, while

Ex. 1028 has a header that includes information such as the copyright ownership of

PR Newswire, “Distribution,” “Section,” “Length,” and “Dateline,” and has the

“Classification” section that includes a “Load-Date,” the page accessible from the

hyperlink does not. Thus, the link itself does not establish the source of Ex. 1028.

The link, like Ex. 1028, also fails to provide any information as to how and

when PR Newswire became aware of the information in Ex. 1028 and uploaded it

to its website. A hyperlink, and especially one that provides no further details

about a document’s potential publication, is insufficient to support a finding of

public accessibility. See Ford, IPR2016-01012, Paper 12 at 8 (existence of

hyperlink was not persuasive of public accessibility before the critical date); see

also, Air Liquide Large Indus. U.S., LP v. Praxair Tech. Inc., IPR2015-01074,

Paper 11 at 6 (P.T.A.B. Oct. 26, 2015) (conference website was insufficient

evidence of availability at the website at the critical date).

Furthermore, the Board has held that a website provided as an exhibit did

not support the public accessibility of a document prior to the critical date 1) when

the petitioner failed to provide any archival evidence of the website, and 2) when

the dates on the exhibit were after the critical date. Google, IPR2015-00789, Paper

8 at 8 (P.T.A.B. Sept. 2, 2015). The situation here is similar. Petitioner fails to

U.S. Patent No. 9,125,939 IPR2017-00287

14

provide any archival evidence of the hyperlink, and Ex. 1028 itself includes

multiple dates, none of which Petitioner explained. At best, the hyperlink supports

only that PR Newswire currently allows access to subject matter substantially

identical to Ex. 1028.

The copyright notice of 2002 likewise fails to provide any evidence as to

when BMS/Otsuka Press Release was made accessible to the public. Indeed, the

Board recently concluded that “[t]he copyright notice, alone, however, sheds

virtually no light on whether the document was publicly accessible as of that date,

therefore additional evidence is typically necessary to support a showing of public

accessibility.” Microsoft Corp. v. Corel Software, LLC, IPR2016-01300, Paper 13

at 10-11 (P.T.A.B. Jan. 4, 2017). Here, the copyright of 2002 does not provide any

information as to when Ex. 1028 was actually published.

2. Petitioner Fails to Establish That Persons Interested in the Art Would Have Been Able to Access BMS/Otsuka Press Release

The mere fact that a document may have existed before the critical date of

the patent is insufficient to establish that the document is a prior art printed

publication. In re Bayer, 568 F.2d 1357, 1360-62 (Fed. Cir. 1978) (holding that an

uncatalogued, unshelved thesis is not a “publication” within the meaning of 35

U.S.C. § 102(b)). Separate and apart from Petitioner’s failure to provide any

support for its assertion that BMS/Otsuka Press Release was published before the

U.S. Patent No. 9,125,939 IPR2017-00287

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critical date (Pet. at 16.), Petitioner has not shown that it was disseminated or

otherwise made available to persons of ordinary skill. SRI Intern., 511 F.3d at

1195.

Petitioner could have attempted to provide evidence demonstrating that

persons interested in the art would have been able to locate BMS/Otsuka Press

Release before the critical date, but it did not do so. As such, Petitioner cannot

establish that BMS/Otsuka Press Release is a prior art printed publication. The

Board held against a petitioner in a similar circumstance where the petitioner failed

to provide any evidence as to how persons interested in the art would have located

the document at issue. See Cisco Sys., Inc. v. Constellation Techs. L.L.C.,

IPR2014-01085, Paper 11 at 9 (P.T.A.B. Jan. 9, 2015) (“Petitioner’s naked

assertion that Rosenberg was published is not supported by the record, which fails

to identify the circumstances and manner in which persons interested and

ordinarily skilled in the subject matter could locate the reference.” (citation

omitted)). The result should be the same here.

3. Petitioner Does Not Provide the Source of BMS/Otsuka Press Release

To establish that a document is a printed publication, at the very least

Petitioner must provide evidence of its source. See, ResQNet.com, Inc. v. Lansa,

Inc., 594 F.3d 860, 865 (Fed. Cir. 2010); Boehringer, IPR2015-00418, Paper 14 at

U.S. Patent No. 9,125,939 IPR2017-00287

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10, 14. Both the Federal Circuit and Board have held that a document is not a

printed publication when the source was not provided as evidence. For example,

the Board in Boehringer found that the petitioner had not explained “how or where

it obtained the ECOG protocols[,]” and ultimately held that the petitioner failed to

establish those protocols were prior art printed publications. IPR2015-00418,

Paper 14 at 10, 14. Here, the origin of Ex. 1028 is unclear, and the hyperlink sheds

no light on its actual source because it leads to a different document altogether.

For all of these reasons, Petitioner has not met its burden to establish that

BMS/Otsuka Press Release is a printed publication, and all of the grounds based on

it should be denied.

III. Even If Certain Documents Constitute Printed Publications, Which Petitioner Has Not Shown, Petitioner Fails to Establish a Reasonable Likelihood that Any Claim is Unpatentable

The Petition proposes six grounds of unpatentability based on obviousness.

The grounds are largely redundant of one another, each essentially mixing and

matching the same documents in different combinations. But no matter how

Petitioner combines its selection of documents, none of its proposed grounds

establishes a reasonable likelihood that any challenged claim is unpatentable as

obvious.

U.S. Patent No. 9,125,939 IPR2017-00287

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A. Petitioner Fails to Establish the Requisite Motivation to Support Its Proposed Grounds of Unpatentability

Petitioner alleges that a person of ordinary skill in the art would have been

motivated to arrive at the challenged claims because one would have generally

expected a combination of atypical antipsychotics with mood stabilizers to

“provid[e] improved efficacy over either agent alone, especially if the patient did

not fully respond to a mood stabilizer monotherapy.” Pet. at 25 (citing “Ex. 1002 ¶

60; Ex. 1009 at 4, 9; see generally Ex. 1002, Appendices A-D”); see also Pet. at

31, 33, 35, 37, 39. Petitioner further asserts that a person of ordinary skill in the art

would have been motivated to combine lithium and aripiprazole to arrive at the

claimed method of treatment. E.g., id. at 27. Petitioner’s arguments, however, are

unsupported by the record.

1. Petitioner Has Not Demonstrated That Atypical Antipsychotics Would Be Added to Mood Stabilizers “Whenever the Mood Stabilizer Was Insufficiently Effective”

To support its alleged motivation, Petitioner relies on Dr. Frances’s opinion

that “[i]n milder cases . . . mood stabilizers would often be started first as

monotherapy, but antipsychotics would be added whenever the mood stabilizer was

insufficiently effective, such as when the patient has shown an inadequate response

U.S. Patent No. 9,125,939 IPR2017-00287

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to the monotherapy.”2 Ex. 1002 ¶ 60 (emphasis added). But Petitioner’s own

documents do not support this. In particular, Expert Consensus states:

2 More often than not, as in this instance, Dr. Frances fails to provide any citations

to support his opinions. Both the Federal Circuit and the Board ascribe “little

probative value” to declaration opinions that lack objective support. DIRECTV,

LLC v. Qurio Holdings, Inc., IPR2015-02006, Paper 6 at 10-11 (P.T.A.B. Apr. 4,

2016) (quoting Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d

281, 294 (Fed. Cir. 1985)). Thus, the Board should not credit Dr. Frances’s

unsupported testimony. See, e.g., Gen. Elec. Co. v. TAS Energy Inc., IPR2014-

00163, Paper 11 at 11 (P.T.A.B. May 13, 2014); see also, e.g., Praxair

Distribution, Inc. v. INO Therapeutics, Inc., IPR2015-00522, Paper 12 at 15

(P.T.A.B. July 29, 2015). The Board should also reject Petitioner’s and Dr.

Frances’s general references to ninety pages of appendix material, i.e.,

“Appendices A-E.” See, e.g., Whole Space Indus. Ltd. v. Zipshade Indus. (B.V.I.)

Corp., IPR2015-00488, Paper 14 at 13-14 (P.T.A.B. July 24, 2015) (denying

consideration of material “not presented and developed in the Petition” as violating

“the particularity and specificity required of supporting evidence” and requiring

the Board to “sift through” thirty-one pages of a Declaration); see also, e.g.,

DIRECTV, IPR2015-02006, Paper 6 at 10 (“[T]he Petition’s consistent citations to

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19

[i]f the patient has had no response to the first mood stabilizer within 1 to 2 weeks, the experts recommend adding or switching to another top-rated mood stabilizer. In contrast, if the patient is showing a partial response, the experts would simply add a second mood stabilizer [not an atypical antipsychotic] after 2 to 3 weeks.

Ex. 1026 at 18.

Similarly, contrary to Petitioner’s assertions, APA Practice Guidelines (Ex.

1009) do not indicate that the combination of any atypical antipsychotic with

lithium or valproate was generally viewed as more effective than those agents

alone. Pet. at 27. Rather, in the short, four-sentence “Combination therapy”

section, only two antipsychotics are mentioned: olanzapine and risperidone. Ex.

1009 at 31, right col. The cited studies themselves identify the findings as

“preliminary.” See id. (citing study “307,” which is titled “Safety and efficacy of

risperidone as combination therapy for the manic phase of bipolar disorder:

preliminary findings of a randomized double blind study” (emphasis added)).

Based on these preliminary studies, APA Practice Guidelines state that the

combination of an atypical antipsychotic with a mood stabilizer “may be more

effective.” Ex. 1009 at 15, left col. (emphasis added).

large portions of the [Expert] Declaration runs afoul of the particularity and

specificity required of supporting evidence under our governing statute and

rules.”).

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As a result, the APA Practice Guidelines later propose future research,

specifically directed to how the potential antimanic effect of one atypical

antipsychotic might compare to another, and in what circumstances combination

therapy may be desirable. See Ex. 1009 at 42 (“Do different atypical

antipsychotics exert different antimanic effects?” “In what circumstances is

combination therapy favored over monotherapy?”). Such aspirational research

goals cannot—as a matter of law—support Petitioner’s case for motivation,

especially where Petitioner has made absolutely no showing to support the

conclusion that results with one atypical antipsychotic translate to aripiprazole, an

atypical antipsychotic different in structure and receptor-binding profile. See, e.g.,

Personal Web Techs., LLC v. Apple, Inc., --- F.3d ----, 2017 WL 587132, at *5

(Fed. Cir. Feb. 14, 2017) (“[O]bviousness concerns whether a skilled artisan not

only could have made but would have been motivated to make the combinations or

modifications of prior art to arrive at the claimed invention.”) (emphases in

original); Star Sci., Inc. v. R.J. Reynolds Tobacco Co., 655 F.3d 1364, 1376 (Fed.

Cir. 2011) (“[S]peculative and tentative disclosure [in the prior art] of what ‘might’

or ‘may’ [result] does not sufficiently direct or instruct one of skill in this art.”).

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2. Petitioner Does Not Argue and Provides No Evidence that Aripiprazole Was Viewed as Interchangeable With Other Atypical Antipsychotics for Bipolar Disorder

While conceding that at the time of the ’939 patent, aripiprazole was “one of

the newest atypical antipsychotics on the market” (Pet. at 14), Petitioner neglects

to mention aripiprazole was first approved by the FDA a mere six months before

the ’939 patent’s priority date only for the short-term treatment of schizophrenia.

Ex. 2006 at 7; Ex. 2007. Petitioner also fails to address that aripiprazole was

known to be unique from all other atypical antipsychotics in chemical structure and

mechanism of action. For example, Exhibit 1023—which Petitioner submitted, yet

nowhere discusses—states that aripiprazole “is a novel antipsychotic with a

mechanism of action that differs from all currently marketed typical and atypical

antipsychotics.” Ex. 1023 at 1; see also Ex. 2002 at 1 (“Aripiprazole is the first

next-generation atypical antipsychotic with a mechanism of action that differs from

currently marketed typical and atypical antipsychotics.”). Even documents

Petitioner relies on in its proposed grounds describe aripiprazole’s distinctiveness.

See Ex. 1008 at 2 (“[A]ripiprazole [is] an antipsychotic with a unique

pharmacologic profile of dopamine D2 partial agonism, serotonin 5HT1A partial

agonism and 5HT2A antagonism.”); Ex. 1028 at 2.

Furthermore, in prior litigation where aripiprazole and its use for treating

schizophrenia were held nonobvious over prior art atypical antipsychotics, the

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district court observed that “[w]ith the exception of aripiprazole, all FDA-

approved atypical antipsychotics are structurally related to either clozapine or

risperidone.” Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 3:07-cv-01000, 2010 WL

4596324, at *3 (D.N.J. Nov. 15, 2010) (emphasis added). In affirming the district

court’s decision, the Federal Circuit reiterated that “[e]very FDA-approved

atypical antipsychotic has a chemical structure related either to clozapine or

risperidone, with the sole exception of aripiprazole.” Otsuka Pharm. Co., Ltd. v.

Sandoz, Inc., 678 F.3d 1280, 1284 (Fed. Cir. 2012) (emphasis added).

Petitioner has not made any effort to demonstrate that aripiprazole’s known

differences compared to other atypical antipsychotics would not have impacted

what a person of ordinary skill in the art would have thought about its potential

interchangeability for olanzapine or risperidone in the treatment of bipolar disorder

generally, in the treatment of bipolar disorder in combination therapy, or in the

specific patient population of the claims.

The only attempted explanation comes not in Petitioner’s “detailed

explanation” of its proposed grounds but instead in the Frances declaration. Here

again, however, Dr. Frances states without citation that “[a] psychiatrist of

ordinary skill would have expected aripiprazole to have the same well-established

pattern of usefulness in combination with mood stabilizing drugs in the treatment

of Bipolar Disorder.” Ex. 1002 ¶ 11. This unsupported assertion cannot serve as a

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basis to establish a motivation to arrive at the challenged claims. See In re

Magnum Oil Tools Int’l., Ltd., 829 F.3d 1364, 1380 (Fed. Cir. 2016) (“To satisfy

its burden of proving obviousness, a petitioner cannot employ mere conclusory

statements.”); see also, e.g., Praxair, IPR2015-00522, Paper 12 at 15; Logic Tech.

Dev., LLC v. Fontem Holdings 1 B.V., IPR2015-00098, Paper 8 at 10 (P.T.A.B.

May 11, 2015); Gen. Elec. Co., IPR2014-00163, Paper 11 at 11; SAS Institute, Inc.

v. ComplementSoft, LLC, IPR2013-00581, Paper 17 at 3-4 (P.T.A.B. Feb. 25,

2014). Moreover, preliminary data involving only two atypical antipsychotics—

olanzapine and risperidone—is the opposite of a “well-established pattern.” Ex.

1009 at 31, right col. Thus, Petitioner’s asserted motivation is unsupported. As a

result, Petitioner fails to establish a reasonable likelihood of prevailing on any

challenged claim.

3. Petitioner’s Remaining Documents Do Not Cure These Deficiencies

Keck and BMS/Otsuka Press Release do not justify the Petitioner’s case of

motivation. These exhibits discuss a clinical study involving aripiprazole

monotherapy compared to placebo. Ex. 1007 at 2; Ex. 1028 at 1. That study did

not involve administering aripiprazole with another agent, comparing aripiprazole

to another agent, or evaluating treatment in a patient population partially

nonresponsive to lithium or valproic acid, divalproex sodium or a salt thereof

U.S. Patent No. 9,125,939 IPR2017-00287

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monotherapy. Indeed, Petitioner and Dr. Frances do not contend that this study

would have informed one of ordinary skill on the prospect of combining

aripiprazole with another agent, much less the claimed combination with lithium

for treating the recited patient population.

Tohen indicates that “the combination of lithium or valproate plus

olanzapine may provide additional efficacy compared with either agent alone.” Ex.

1006 at 7 (emphasis added). Here again, Petitioner extrapolates without

explanation these preliminary findings concerning olanzapine in combination with

a mood stabilizer to all atypical antipsychotics, including aripiprazole. See Pet. at

31. The Petition provides no basis for broadening Tohen’s disclosure to all

atypical antipsychotics, let alone to aripiprazole with its distinct chemical structure

and mechanism of action. See Ex. 1023; supra § III.A.2.

Expert Consensus (Ex. 1026) does not even mention the preliminary

findings concerning olanzapine and risperidone that were referenced in the short

“[c]ombination therapy” paragraph in APA Practice Guidelines (Ex. 1009 at 31).

Thus, it lends no support to Petitioner’s theory that preliminary findings for certain

atypical antipsychotics would have been extrapolated to all atypical antipsychotics,

including aripiprazole. See infra § IV.C.5.

Citrome summarizes a clinical study assessing the safety of coadministering

aripiprazole with lithium or divalproex sodium in patients with schizophrenia or

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schizoaffective disorder. Ex. 1008 at 2. The Petition does not contend that a safety

study involving a different indication and patient population would have informed

one of ordinary skill as to the efficacy of the claimed combination therapy to treat

bipolar disorder in a patient partially nonresponsive to lithium or valproic acid,

divalproex sodium or a salt thereof monotherapy. See Pet. at 38, 40. Indeed, the

supposed safety of the combination of lithium and aripiprazole is insufficient to

establish any motivation or reasonable expectation of success regarding its efficacy

in the claimed patient population. Thus, Citrome also provides no basis for

Petitioner’s asserted motivation. See infra § IV.C.3.

B. Petitioner Provides No Basis to Support a Reasonable Expectation of Success

Obviousness requires that one of ordinary skill would have had a reasonable

expectation of success in making the claimed invention. See Broadcom Corp. v.

Emulex Corp., 732 F.3d 1325, 1335 (Fed. Cir. 2013); Amgen Inc. v. F. Hoffman-La

Roche Ltd., 580 F.3d 1340, 1362-63 (Fed. Cir. 2009). Here, the Petition mentions

the phrase “reasonable expectation of success” in passing but provides no evidence

that a combination of aripiprazole and lithium would have been reasonably

expected to treat bipolar disorder in the claimed patient population, namely “in a

patient partially nonresponsive to lithium or valproic acid, divalproex sodium or a

salt thereof monotherapy.” As the Federal Circuit has explained, “[i]t is of the

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utmost importance that petitioners in the IPR proceedings adhere to the

requirement that the initial petition identify with particularity the evidence that

supports the grounds for the challenge to each claim.” Intelligent Bio-Sys., Inc. v.

Illumina Cambridge Ltd., 821 F.3d 1359, 1369 (Fed. Cir. 2016) (internal

quotations omitted). Nowhere does Petitioner or Dr. Frances account for (1)

aripiprazole’s distinctive chemical structure and mechanism of action compared to

all other marketed antipsychotics at the time (supra § III.A.2.), or (2) treating

bipolar disorder in the claimed patient population using a combination of

aripiprazole and lithium. Accordingly, Petitioner fails to carry its burden, and the

Petition should be denied.

1. Petitioner Does Not Account for Aripiprazole’s Distinctiveness

Aripiprazole is not olanzapine or risperidone. In fact, the record evidence

recognizes aripiprazole as distinct from not only those atypical antipsychotics, but

all marketed typical and atypical antipsychotics at the time of the ’939 patent.

Supra § III.A.2. The question, then, is why would a person of ordinary skill have

reasonably expected aripiprazole to be effectively interchangeable with olanzapine

or risperidone as a combination therapy for bipolar disorder in the claimed patient

population? The Petition does not answer this question. This alone requires denial

of the Petition.

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For example, in a case involving a method of treatment for narcolepsy where

a patient was given GHB in a dose that was reduced by at least 5% from a typical

effective dose when the patient received a concomitant administration of valproate,

the Board denied institution, concluding inter alia that Petitioner had not

established a reasonable expectation of success. Par Pharm. Inc. v. Jazz Pharm.

Ireland Ltd., IPR2016-00002, Paper 12 at 4, 13-14 (P.T.A.B. Apr. 12, 2016).

Specifically, although the prior art suggested that valproate might intensify the

effect of GHB, thus producing an expectation that a lower dose would still be

efficacious, the record evidence also showed that the body eliminated GHB

through alternative pathways not inhibited by valproate. Id. at 13. Petitioner did

not provide any evidence that valproate alone could have “predictably”

compensated for the GHB lost through these alternative routes. Id. at 13-14.

Likewise, here, Petitioner does not demonstrate that one would have—or

even could have—predictably translated preliminary findings for olanzapine or

risperidone in combination with mood stabilizers to the claimed combination of

aripiprazole and lithium. In fact, Petitioner’s own declarant admits that drug

interactivity is highly unpredictable. See Ex. 1004 at Appendix A ¶ 20.

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2. Petitioner Does Not Account for the Claimed Patient Population

a. The Preamble Is Limiting

Under well-settled legal principles and as confirmed by the prosecution

history, “treating bipolar disorder in a patient partially nonresponsive to lithium or

valproic acid, divalproex sodium or a salt thereof monotherapy” limits each

challenged claim. Petitioner does not argue otherwise. Indeed, it proposes a

construction for the recited patient population. Pet. at 10.

Thus, to carry its burden, the Petition must identify, with particularity,

evidence that a person of ordinary skill in the art would have reasonably expected a

combination of aripiprazole and lithium administered in the claimed amounts to be

effective to “treat[] bipolar disorder in a patient partially nonresponsive to lithium

or valproic acid, divalproex sodium or a salt thereof monotherapy.” See DePuy

Spine, Inc v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009)

(“[T]he ‘predictable result’ discussed in KSR refers not only to the expectation that

prior art elements are capable of being physically combined, but also that the

combination would have worked for its intended purpose.”). This it does not do.

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b. Petitioner Fails to Provide Any Evidence that a Combination of Aripiprazole and Lithium Would Have Been Reasonably Expected to Treat Bipolar Disorder in the Claimed Patient Population

For each proposed ground, Petitioner’s only evidence for a reasonable

expectation of success is Dr. Frances’s testimony, which has no citations to any

record evidence and essentially mimics the language of the Petition. Compare,

e.g., Pet. at 33 with Ex. 1002 ¶ 92, Pet. at 27 with Ex. 1002 ¶ 64, Pet. at 31-32 with

Ex. 1002 ¶ 74, Pet. at 36 with Ex. 1002 ¶ 74, Pet. at 38 with Ex. 1002 ¶ 82, Pet. at

40 with Ex. 1002 ¶¶ 86-87. As such, Petitioner fails to meet its burden to identify

with particularity evidence to support its obviousness challenge. Intelligent Bio-

Sys., 821 F.3d at 1369.

Further, Petitioner’s unsupported contention that one of ordinary skill would

have understood all atypical antipsychotics in combination with mood stabilizers to

be “generally more effective than monotherapy” (Pet. at 27) on its face fails to

account for “patients partially nonresponsive to lithium or valproic acid, divalproex

sodium or a salt thereof monotherapy.” The same holds true for Petitioner’s

generic assertion that “aripiprazole, which was new to the market, was safe and

effective in treating bipolar disorder.” Pet. at 27. Notably, Petitioner does not

address the recognized uncertainty inherent in successfully treating bipolar

disorder in patients who are refractory to first-line treatment. See Ex. 1026 at 8

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(“[T]here are many situations for which there are no well-controlled data, such as

key drug-drug comparisons or the management of illness that is refractory to first-

line treatments.” (emphasis added)). And Petitioner likewise ignored its own

document’s disclosure that results regarding aripiprazole in bipolar disorder

generally were equivocal at the time. Ex. 1028 at 1 (“In a second placebo-

controlled study . . . aripiprazole did not show statistical separation from

placebo.”).

The Board has previously denied institution under similar circumstances,

specifically where a petitioner failed to adequately account for a particular patient

population. Phigenix, Inc. v. Genentech, Inc., IPR2014-00842, Paper 10 at 15-16

(P.T.A.B. Dec. 9, 2014). There, the claims related to a “tumor characterized by

overexpression of ErbB2 receptor and that does not respond, or responds poorly,

to treating with an anti-ErbB antibody [HERCEPTIN®].” Id. at 5. The prior art

taught that some patients failed to respond to HERCEPTIN®, and that

HERCEPTIN® increased the effectiveness of chemotherapy in patients who

responded to HERCEPTIN® and chemotherapy. Id. at 15. The petitioner

attempted to take this disclosure a step further, arguing it suggested that “patients

unresponsive to HERCEPTIN® would respond to the HERCEPTIN® antibody, if

administered with chemotherapy.” Id. at 15-16 (emphasis added). But petitioner’s

assertion failed to account for the claimed patient population, and the Board thus

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concluded that it had not established a reasonable expectation of success. Id. at 16.

The result should be no different here.

Moreover, the Board routinely denies petitions for failing to sufficiently

address a claim element. For example, in Intelgenx Corp v. ICOS Corp., the Board

denied institution of inter partes review on a claim directed to “[a] method of

treating sexual dysfunction” comprising administering a compound in “one or

more unit dose containing about 1 to about 20 mg, up to a maximum total dose of

20 mg per day.” IPR2016-00678, Paper 13 at 3 (P.T.A.B. Sept. 1, 2016). The

petitioner alleged that one of ordinary skill would have reasonably expected doses

in the claimed range to provide “therapeutic efficacy for treating sexual

dysfunction.” Id., Paper 1 at 28. But the petitioner failed to provide any evidence

to account for the “up to a maximum total dose of 20 mg per day” limitation.

Citing this failure alone, the Board observed that “all patent claim terms are

presumed to have meaning” and necessarily denied institution for failing to

establish a reasonable likelihood of prevailing on any challenged claim. Id., Paper

13 at 6-7; see also, e.g., Jiawei Tech. (HK) Ltd. v. Richmond, IPR2014-00937,

Paper 22 at 7-8 (P.T.A.B. Dec. 16, 2014) (denying institution where petitioner’s

explanation for how a skilled artisan would have arrived at the challenged claims

glossed over a claim limitation).

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Similarly, here, the preamble is limiting, and Petitioner fails to explain with

any particularity how an ordinary artisan would have reasonably expected a

combination of aripiprazole and lithium to treat bipolar disorder in the claimed

patient population.

3. Petitioner’s Allegation of Reasonable Expectation of Success Impermissibly Relies on the ’939 Patent Specification

In a footnote, Petitioner attempts to justify its deficient analysis by pointing

to the ’939 patent specification and what the inventors reasonably expected. Pet. at

27-28 n. 4.3 This is legally improper. 35 U.S.C. § 103(a) (“Patentability shall not

be negatived by the manner in which the invention was made.”); see KSR Int’l v.

Teleflex Inc., 550 U.S. 398, 421 (2007) (warning against a “temptation to read into

the prior art the teachings of the invention in issue” and instructing courts to

“guard against slipping into use of hindsight”); Life Techs. v. Clontech Labs., Inc.,

224 F.3d 1320, 1325 (Fed. Cir. 2000) (“[T]he path that leads an inventor to the

invention is expressly made irrelevant to patentability by statute.”).

3 Patent Owner disagrees with Petitioner’s characterization of the ’939 patent in

this footnote.

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IV. Petitioner’s Grounds Should Be Denied as Redundant to the Art and Arguments Previously Considered and Overcome During Prosecution

A. The Board Should Deny Institution Where the Same or Substantially the Same Prior Art or Arguments Were Previously Presented

Under 35 U.S.C. § 325(d), the Board has discretion to deny petitions that

raise the same or substantially the same prior art or arguments that were previously

presented to the Office, including during prosecution. This discretion gives the

Office control over its own resources and ensures that post-grant proceedings are

not tools for harassment. See Apotex Inc. v. OSI Pharms., Inc., IPR2016-01284,

Paper 8 at 7 (P.T.A.B. Jan. 9, 2017) (citing H.R. REP. No. 112-98, pt.1 at 48

(2011); Lower Drug Prices for Consumers, LLC v. Forest Labs. Holdings Ltd.,

IPR2016-00379, Paper 14 at 2, 6-12 (P.T.A.B. July 1, 2016) (“readjudicating

substantially the same prior art and arguments as those presented during

prosecution would not be an efficient use of Board resources”); see also Mylan

Pharms. Inc. v. Yeda Research & Dev. Co., PGR2016-00010, Paper 9 at 6-10

(P.T.A.B. Aug. 15, 2016) (denying institution of PGR where Office already

considered the issue of whether the application was a pre-AIA or AIA application).

Petitioners do not escape § 325(d) simply by raising new art or combinations

of art. Rather, the relevant inquiry is whether petitioner presents substantially the

same issues. See Neil Ziegmann, N.P.Z., Inc. v. Stephens, IPR2015-01860, Paper

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11 at 2, 10 (P.T.A.B. Feb. 24, 2016); PRISM Pharma Co. v. Choongwae Pharma

Corp., IPR2014-00315, Paper 14 at 12-13 (P.T.A.B. July 8, 2014) (informative

decision). Indeed, recently the Board concluded that it could exercise its discretion

under § 325(d) even where the exact combination of prior art and an altogether

new reference were not considered during prosecution. Kayak Software Corp. v.

Int’l Bus. Machs. Corp., CBM2016-00075, Paper 16 at 7-12 (P.T.A.B. Dec. 15,

2016). In such a situation where there were no “clear errors” made during

prosecution, and petitioner did not identify any circumstances of material change,

such as changed claim constructions or new evidence regarding priority dates, the

Board chose to use its discretion under § 325(d). Id. at 11.

Here, Petitioner makes the same arguments that the Examiner made and

ultimately withdrew based on identical or cumulative disclosures. Moreover,

Petitioner does not identify any clear errors or material changes that should

preclude the Board from exercising its discretion.

B. Summary of the Prosecution of the ’939 Patent

Applicant filed U.S. Patent Application No. 10/556,600 (“the ’600

application”), which led to the ’939 patent on November 14, 2005. The ’600

application is a national stage application under § 371 that claims the benefit of

priority of U.S. Provisional Application No. 60/473,378, filed on May 23, 2003.

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The Office issued a first Office Action on the merits on April 30, 2009. Ex. 1076

at 928-50. At the time, original claim 12 recited:

[a] method of treating a mood disorder in a patient comprising separate administration of a first amount of a carbostyril derivative and a second amount of mood stabilizer, wherein the administration is effective to treat the mood disorder in the patient.

Id. at 88-89. Original dependent claim 13 limited the carbostyril derivative to

aripiprazole or a metabolite thereof; and claim 15 specifically listed lithium among

other mood stabilizers.

The Examiner rejected the pending claims, including claims 12, 13, and 15,

inter alia, as being obvious over Kowatch et al. (CNS Spectrum (April 2003)

8(4):273-80, Ex. 1010, “Kowatch”). Id. at 944-45. The Examiner also rejected

claim 14, directed to specific metabolites, as being obvious over Kowatch in

combination with U.S. Patent Application Publication No. 2002/0173513 (Ex.

2003, “Jordan”). Id. at 944-46.

In making its rejections, the Examiner stated that Kowatch discloses “that

Lithium is a well known mood stabil[i]zer and compositions containing Lithium

are used for treating bipolar disorder, acute mania.” Id. at 944. In addition, the

Examiner stated that Kowatch “also discloses atypical antipsychotics such as

Aripiprazole . . . is effective in treating bipolar disorder.” Id. Further, the

Examiner pointed out that Kowatch also taught that the combination of lithium and

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an atypical antipsychotic, specifically olanzapine and quetiapine, “decreases

bipolar symptoms and improve[s] overall response rates” compared to

monotherapy. Id. at 944-45. Based on these disclosures, the Examiner concluded

that

[i]t would have been obvious to a person of ordinary skill in the art at the time of invention to combine atypical antipsychotic agent, aripiprazole with lithium because Kowatch teaches that the combination of atypical antipsychotic with lithium gives better overall response in the method of treating bipolar disorder. It is generally considered prima faci[e] obvious to combine compounds each of which is taught by the prior art to be useful for the same purpose, in order to form a composition which is used for the very same purpose i.e. for treating bipolar disorder.

Id. at 945. Regarding the rejection of claim 14, the Examiner stated that Jordan

discloses that carbostyril derivatives, including aripiprazole and one of its

metabolites, dehydroaripirazole, “are useful in treating bipolar disorders.” Id. at

946.

After an extensive examination spanning six years, the Examiner allowed

the claims that ultimately issued. Ex. 1076 at 967-69, 970, 1022, 1047-48, 1049,

1051, 1077, 1096-97, 1099, 1106, 1126, 1144, 1149, 1176, 1197, 1199, 1224,

1243, 1258, 1219, 1224, 1258, 1279, 1291-99. Over the course of prosecution, the

Examiner repeatedly rejected—as admitted by Petitioner—“claims substantially

corresponding to claims 2, 6, 7, and 9.” Pet. at 7; see e.g., Ex. 1076 at 1053-58,

U.S. Patent No. 9,125,939 IPR2017-00287

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1107-12, 1150-53, 1200-02, 1259-60 (claims 29-30, 34-35, 43, 44, 46). Contrary

to Petitioner’s assertions, however, those rejections were not limited to Kowatch.

See Pet. at 7. In fact, Applicant submitted and specifically referred to the results of

Tohen (Ex. 1006), which are disclosed in Kowatch. Ex. 1076 at 987, 1268, see

also 956 (Tohen considered by Examiner); Ex. 1010 at 8. The Examiner then used

that disclosure in support of an obviousness rejection, stating that Tohen

“disclose[s] that response rate was significantly higher in the combination

treatment with atypical antipsychotic (olanzapine) and valproate or lithium,” and

that the study “include[d] patients partially nonresponsive to valproate or lithium.”

Ex. 1076 at 1133, see also 1231. The Examiner additionally cited Clinical Trial

Report, CN138-00ST (Ex. 2004, “Clinical Trial Report”) to assert “that

aripiprazole is useful in treating acute mania episode.” Id. at 1180. Moreover,

Applicant submitted Citrome et al., Pharmacokinetics and Safety of Aripiprazole

and Concomitant Mood Stabilizers, 5 INT’L J. NEUROPSYCHOPHARMACOLOGY,

S187, P.4.E. 035 (Ex. 2005, “Citrome S187”), which is identical in content to

Petitioner’s Citrome (Ex. 1008) except for the conference details.4 Id. at 1046.

The Examiner considered that abstract (id.), but did not apply it against the claims.

4 Just as was noted during prosecution, Patent Owner makes no admission that

Citrome S187 is prior art or a printed publication. See Ex. 1076 at 1044.

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Throughout prosecution, Applicant repeatedly argued that the Office had not

established a prima facie case of obviousness against any of the pending claims.

Ex. 1076 at 970, 1051, 1106, 1149, 1199, 1258. For example, in its last response,

Applicant urged the Examiner to consider the prior art as a whole (as must be

done). Id. at 1268. Applicant asserted that Kowatch discloses nothing more than

results from multiple studies using certain atypical antipsychotics in combination

with lithium or valproate in specific patient populations that differed from one

another, none of which included the combination of aripiprazole and lithium. Id. at

1268-69. Thus, Applicant asserted that “[i]t remains unclear what basis the Office

uses to extrapolate from Kowatch’s combination summary to the presently pending

claims” absent hindsight. Id. at 1269.

As part of its case in support of patentability, Applicant submitted a

declaration from Dr. Hirose, an inventor of the ’939 patent, which included data

from experiments in a mouse model for mania. Id. at 1156, 1160-64. Applicant

asserted that the observed results were “unpredictable from the disclosure of the

prior art references, which fail to teach or suggest a synergistic effect achieved by

an atypical antipsychotic and mood stabilizer.” Id. at 1156. In two subsequent

Office Actions, the Examiner raised several questions about the Hirose data. Id. at

1184-86, 1229-30. And Applicants addressed each point. Id. at 1207-08, 1266,

1279-80. Thereafter, based on both Applicant’s arguments and Dr. Hirose’s

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declaration, the Examiner allowed the claims. Id. at 1282 (“Office agreed to

consider the data and arguments”), 1296.

C. Petitioner Relies on the Same or Cumulative Documents and Uses Them in the Same Way the Examiner Did

Petitioner’s six grounds of alleged unpatentability are based on either

identical disclosures (Tohen and Citrome) or disclosures that are cumulative

(Keck, BMS/Otsuka Press Release, APA Practice Guidelines, Expert Consensus)

of the art raised, considered, and rejected by the Examiner during prosecution.

Moreover, Petitioner relies on these identical or substantially similar disclosures to

support its alleged obviousness case in the same way that the Examiner did.

1. Keck and BMS/Otsuka Press Release are Cumulative of Clinical Trial Report

Keck and the BMS/Otsuka Press Release serve as Petitioner’s secondary

documents in Grounds 1-4 and 6. Petitioner relies on Keck for the proposition that

“aripiprazole was effective and well-tolerated in the treatment of acute mania in

patients with bipolar disorder,” and that “there was no significant changes in

weight for patients taking aripiprazole compared to placebo.” Pet. at 26, see also

14-15; Ex. 1002 ¶ 34. Petitioner relies on the BMS/Otsuka Press Release for the

very same points. Pet. at 26, see also 15-16; Ex. 1002 ¶ 35.

The Examiner relied on Clinical Trial Report to reject the claims, asserting

that it “teaches that aripiprazole is useful in treating acute mania episode.” Ex.

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1076 at 1180. Clinical Trial Report discloses the design and results of a Phase III

study comparing aripiprazole against the typical antipsychotic haloperidol in acute

mania. Ex. 2004 at 1. The conclusions of the study indicate that aripiprazole was

found to be superior to haloperidol, and that it was safe and better tolerated than

haloperidol. Id. at 9. The number of patients with significant weight gain was

similar between the two treatment groups. Id.

Thus, Keck and BMS/Otsuka Press Release, which Petitioner has not

established are printed publications, are cumulative to the Clinical Trial Report on

the very same points for which both Petitioner and the Examiner relied on them.

2. Tohen is Tohen

Petitioner relies on Tohen as its primary document in Ground 2 and as a

secondary document in Grounds 4 and 6. As mentioned, Applicant raised and the

Examiner considered and applied Tohen’s disclosure against the pending claims.

Specifically, the Examiner rejected the claims over Kowatch, which summarizes

the results of Tohen. Ex. 1010 at 8, right-hand col. Applicant noted Tohen’s

disclosures. Ex. 1076 at 987, 1268. And the Examiner specifically referred to

Tohen itself in rejecting the claims. Id. at 1133, 1231.

In Grounds 2, 4, and 6, Petitioner relies on Tohen for its disclosure that

compared with the use of valproate or lithium alone, “the addition of olanzapine

provided superior efficacy in the treatment of manic and mixed bipolar episodes,”

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and that from this disclosure a person of ordinary skill would have understood that

a combination of lithium and an atypical antipsychotic was effective in treating

bipolar disorder in patients partially non-responsive to lithium or valproate

monotherapy. Pet. at 31. Petitioner therefore concludes that a person of ordinary

skill seeking to improve monotherapy with a mood stabilizer would have been

motivated to vary the olanzapine and lithium combination of Tohen by substituting

olanzapine with aripiprazole. Id.

That sequence of argumentation is identical to the Examiner’s. First, the

Examiner stated that Tohen discloses that “response rate was significa[n]tly higher

in the combination treatment with atypical antipsychotic (olanzapine) and

valproate or lithium.” Ex. 1076 at 1133. Second, the Examiner pointed out that

Tohen includes patients partially nonresponsive to valproate or lithium. Id. And

finally, based on these disclosures, the Examiner concluded that one of ordinary

skill in the art would have been motivated to administer a combination of atypical

antipsychotic agent, aripiprazole and lithium with a reasonable expectation of

success for treating bipolar disorder in the claimed patient population. Id. at 1134,

see also 1231-32.

3. Citrome is Almost Citrome S187

Petitioner relies on Citrome as its primary document in Grounds 5 and 6,

although it is not readily apparent that Citrome is actually the base document. Pet.

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at 37-41. While Petitioner has not established that Citrome is a printed publication,

and Patent Owner makes no admission that Citrome S187 (Ex. 2005) is prior art to

the challenged claims, ResQNet.com, 594 F.3d at 866, the substance of Citrome

(Ex. 1008) was submitted to the Office by Applicant as Citrome S187 and

considered by the Examiner. Ex. 1076 at 1046.

Petitioner relies on Citrome for its disclosure that lithium and aripiprazole

were co-administered to patients with schizoaffective disorder and schizophrenia.

Pet. at 38. Petitioner further relies on Citrome for its doses allegedly falling within

the scope of the claims, as well as for the proposition that a person of ordinary skill

in the art would have expected co-administration of lithium and aripiprazole to be

safe. Id. Petitioner also contends that “[a]lthough the patient population in

Citrome was suffering from schizophrenia and schizoaffective disorder, [it]

demonstrate[s] that the ordinarily-skilled artisan had already employed a

combination of aripiprazole and lithium to treat mania.” Pet. at 38 n.5 (emphasis

added). Petitioner cites absolutely no evidence to support this latter contention.

Citrome itself says nothing about mania, let alone treating it. See Ex. 1008. And

neither of the paragraphs of Dr. Frances’s declaration that Petitioner cites, 37 and

81, says anything about mania or the treatment of it. Given that the Citrome study

was an open-label study with only thirteen patients and no control groups, it could

not have established that the co-administration of lithium with aripiprazole was

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effective to treat the schizoaffective and schizophrenic patients in the trial, let

alone any mania (not even mentioned as being observed in the first place). See

also supra § III.A.3.

Thus, the Examiner correctly gave Citrome little weight in assessing the

claims during prosecution.

4. APA Guidelines are Cumulative of Kowatch

Petitioner relies on the APA Guidelines as its primary document in Ground 1

and as a secondary document in Grounds 4 and 5. Referring only to pages 4, 9, 10,

and 25 (i.e., pages 10, 15, 16, and 31 according to the pagination in the footer) of

the fifty-plus pages of the APA Guidelines, Petitioner relies on those discrete

disclosures for the propositions that 1) lithium plus an antipsychotic or valproate

plus an antipsychotic is a “first-line” treatment for “more severe manic or mixed

episodes”; 2) those combination treatments may be more effective than any of the

agents alone; and 3) atypical antipsychotics are preferred over typical psychotics

because of their more benign side effect profile. Pet. at 18-19; Ex. 1002 ¶ 28.

APA Guidelines is cumulative of Kowatch, which the Examiner extensively

considered during prosecution. Regarding Petitioner’s first point, Kowatch states

that “[c]urrent clinical practice is to treat mood episodes in children and

adolescents with bipolar disorders, much as one would adults with these disorders,

using mood stabilizers [lithium] and antipsychotics.” Ex. 1010 at 3 (emphasis

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added). Kowatch further states that “atypical antipsychotics are very powerful

psychotropics that have recently been found to be efficacious in the treatment of

adults with schizophrenia and acute bipolar mania.” Id. at 7.

Regarding the second point, Kowatch states that “[t]here is emerging data

from adult and child studies that the addition of an atypical antipsychotic to a

mood stabilizer may decrease bipolar disorder symptoms and improve overall

response rates.” Id. at 8. Moreover, Kowatch summarizes the results of studies

with lithium and valproate tested in combination with atypical antipsychotics,

olanzapine (Tohen) and quetiapine. Id. The Tohen study demonstrated that the

“response rate was significantly higher in the combination group.” Id. In the

quetiapine study, Kowatch states that “[t]he findings of this study indicate that

quetiapine in combination with valproate was more effective for the treatment of

adolescent bipolar mania than valproate alone.” Id.

And finally, the Clinical Trial Report disclosed that aripiprazole was safe

and well tolerated in the patient population tested. Ex. 2004 at 9. Thus,

Petitioner’s reliance on only certain disclosures of the APA Guidelines is entirely

cumulative of documents already extensively considered by the Examiner.

Moreover, Petitioner’s arguments about the APA Guidelines directly mirror

those the Examiner made regarding Kowatch and Tohen. Specifically, Petitioner

states that the APA Guidelines taught that lithium, valproate, and antipsychotic

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medications had shown efficacy in the treatment of patients with acute mania, and

that the combination therapy was “already viewed as more effective than either

agent alone,” “especially if the patient did not fully respond to a mood stabilizer

monotherapy.” Pet. at 25. From this, Petitioner concludes that a person of

ordinary skill in the art would have looked to use a combination therapy of lithium

and an atypical antipsychotic. Id. at 25-26.

The Examiner made the exact same findings and drew a similar conclusion

regarding Kowatch (and Tohen). In particular, the Examiner stated that Kowatch

“taught that addition of atypical antipsychotic, olanzapine, quetiapine to a mood

stabilizer such as lithium decreases bipolar symptoms and improve overall

response rates than monotherapy.” Ex. 1076 at 1129 (emphasis in original). The

Examiner thus concluded that it would have been obvious to use lithium and

aripiprazole to treat bipolar disorder “because Kowatch teaches that addition of

a[n] atypical antipsychotic to lithium gives better overall response in the method of

treating bipolar disorder i.e. one can treat patients more effectively than

monotherapy.” Id. at 1130 (emphasis in original). Petitioner’s current arguments

are no different.

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5. Expert Consensus Adds Nothing to the Art the Examiner Considered

Petitioner relies on only five discrete disclosures from over 100 pages of

Expert Consensus to support one of its unpatentability challenges (Ground 3). Pet.

at 19-20, 23 (Ground 3 only); Ex. 1002 ¶¶ 29-30. Petitioner asserts that Expert

Consensus recommended antipsychotics as first line in the treatment of mania or

depression with psychosis, and as potential adjuncts in non-psychotic episodes.

E.g., Ex. 1002 ¶ 29. Dr. Frances relies on Expert Consensus for the teaching that

atypical antipsychotics, such as olanzapine and risperidone, were generally

preferred over conventional antipsychotics. Id. Petitioner further points out that if

treatment with the combination of a mood stabilizer and antipsychotic was not

providing the desired therapeutic result, Expert Consensus recommended

substituting the antipsychotic before substituting the mood stabilizer. Id. (Patent

Owner notes that Expert Consensus actually says that “it may be appropriate to

change the antipsychotic earlier than the mood stabilizer.” Ex. 1026 at 19

(emphasis added).) Finally, Petitioner notes that the combination treatment of

mood stabilizer and atypical antipsychotics are either the treatment of choice or an

alternative treatment for different types of mania. Ex. 1002 ¶¶ 29-30.

Petitioner’s laser focus on only five isolated parts of Expert Consensus fails

to provide a fair characterization of the document and its purpose. When

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considered in its entirety, one quickly realizes that Expert Consensus is not only

cumulative to other documents considered during prosecution, but it is not actually

supportive of Petitioner’s positions.

The Expert Consensus is exactly what its title suggests—a compilation of

survey results from experts in the field. Because it is not an analysis of clinical

trial results but instead relies on input from 58 practitioners, the Consensus authors

caution of its limitations. Notably, it states that “[w]e have relied on expert

opinion precisely because we are asking crucial questions that are not yet well

answered by the literature.” Ex. 1026 at 12. And further notes that history teaches

that expert opinion “at any given time can be very wrong.” Id.

Contrary to Petitioner’s assertions that Expert Consensus somehow conveys

that atypical antipsychotics are well-established treatments for bipolar disorder, it

instead refers to divalproex and lithium as “the cornerstone choices among this

class for both acute and preventive treatment of mania.” Id. at 5. The report

further notes that “[r]egardless of which is selected first, if monotherapy fails, the

next recommended intervention is to use these agents [lithium or divalproex] in

combination.” Id. And while experts who were polled supported the use of

atypical antipsychotics, “they still hesitate to recommend them over traditional

mood stabilizers for monotherapy in mania.” Id. at 11. In fact, the Expert

Consensus notes only that adding an antipsychotic “may also be helpful in other

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types of mania,” but again, that is not the recommended preferred initial treatment.

Id. at 16-17. Indeed, what the panel actually recommended is that antipsychotics

should be reserved for “more severe cases,” noting that this recommendation “is

the same as in the last survey and is consistent with clinical tradition rather than

clear-cut data.” Id. at 11. Consistently, the authors state that “[e]xperts reserve

strongest support for initial strategies and individual medications for which there

are high-quality research data, or for which there are longstanding patterns of

clinical usage.” Id. at 5.

Thus, considered as a whole, Expert Consensus does not paint the picture

that Petitioner hopes that it would. Indeed, unlike Kowatch, which was extensively

considered during prosecution, there is no section in Expert Consensus that

discusses clinical trials of using a mood stabilizer and an atypical antipsychotic in

any form of bipolar disorder. See Ex. 1026 at 10-11 (discussing only clinical trials

using atypical antipsychotics as monotherapy); supra § III.A.3. Thus, Petitioner

fails to establish that Expert Consensus is somehow closer prior art than Kowatch,

which the Examiner deemed to be “the closest prior art.” Ex. 1076 at 1296.

6. Conclusion

As shown, Petitioner’s cited documents and arguments are all but identical

to the disclosures and arguments presented and correctly withdrawn by the Office

during examination. On that basis alone, the Board would be well within its

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discretion to deny institution here. And Petitioner’s additional allegations

regarding side effects and unexpected results do not establish any clear error or

raise material changes that warrant institution.

D. Petitioner’s “Side Effects” Arguments Are Irrelevant

Petitioner focuses on aripiprazole’s favorable side effect profile to support

motivation. E.g., Pet. at 26-27. That focus, however, does not preclude the Board

from exercising its discretion under § 325(d). Petitioner notes that atypical

antipsychotics generally were known to have “benign” side effect profiles. Id. at

25. The only additional benefit Petitioner identifies for aripiprazole is related to

weight gain. Id. at 26. But the Examiner considered the Clinical Trial Report,

which stated that “aripiprazole was safe and better tolerated than haloperidol,” and

that “the number of patients with significant weight gain was similar between the

two treatment groups.” Ex. 2004 at 9. Moreover, side effects are largely irrelevant

where Petitioner—like the Examiner—made no effort to demonstrate that

aripiprazole is interchangeable based on its efficacy with an atypical antipsychotic

in the claimed method. Supra § III.A.2. See Daiichi Sankyo Co. v. Matrix Labs.,

Ltd., 619 F.3d 1346, 1353-54 (Fed. Cir. 2010).

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E. Petitioner’s Arguments Regarding Dr. Hirose’s Declaration Are Irrelevant and Do Not Undermine the Examiner’s Conclusions Regarding Patentability

Petitioner asserts that the experimental evidence Applicant submitted during

prosecution cannot support the nonobviousness of the challenged claims. Pet. at

41-49 (citing Ex. 1004). Those arguments, however, should not keep the Board

from using its discretion to deny institution. The Examiner carefully considered

Dr. Hirose’s declaration and Applicant’s arguments regarding it. And Petitioner

fails to establish (indeed does not even contend) that the data itself or the

calculations are wrong. Rather, Petitioner’s expert Dr. Au quibbles with the

experimental design, raising issues that are irrelevant or easily dismissed. In fact,

Dr. Au’s own opinions demonstrate that a person of ordinary skill would have

struggled to have any expectation, let alone a reasonable expectation of success,

about the claimed method of treatment, making the submission of any data

unnecessary.

1. The Hirose Data

In support of the patentability of the pending claims, Applicant submitted a

declaration from Dr. Hirose, one of the inventors on the ’939 patent. Ex. 1076 at

1160-64. Dr. Hirose tested the co-administration of aripiprazole and lithium or

olanzapine and lithium in a well-known and accepted animal model for the manic

condition associated with bipolar disorder. Id. at 1161; Ex. 1004 ¶ 44. In that

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model, mice are given methamphetamine, which stimulates their locomotion. That

locomotion may be potentiated by an active agent, thus providing insight on a

compound’s potential effect in mania. E.g., Ex. 1004 ¶ 45.

To generate the data in his declaration, Dr. Hirose relied on a testing

paradigm where the active agents (aripiprazole, olanzapine, and lithium) were

given together at doses that when given alone generated no response, i.e., a sub-

therapeutic dose. Ex. 1076 at 1208, see also 1265-66. Specifically, mice were

administered either 1) vehicle 1 + 2 + 3; 2) vehicle 1 + 2 + methamphetamine; 3)

vehicle 2 + aripiprazole + methamphetamine; 4) vehicle 1 + LiCl (e.g., “lithium”)

+ methamphetamine; or 5) aripiprazole + LiCl + methamphetamine. Id. at 1162.

The same experimental setup was used for an olanzapine arm. Id. Those groups

and their results are reproduced from the prosecution file history in Ex. 2008 with

experiment numbers for clarity.

In the table, “###” indicates that the all vehicle groups (1 and 6) showed a

statistically significant difference in locomotor count from the methamphetamine

groups in both the aripiprazole (2) and olanzapine (7) arms. Id. That means that

the dose of methamphetamine administered actually increased locomotor counts to

an extent beyond that attributed to chance.

To analyze the rest of the treatment groups, the data was analyzed using a

two-tailed Dunnett’s test. Id. Such a test, as noted by Dr. Au, appropriately

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compares each of several experimental treatments against one control. Ex. 1004

¶ 86. Thus, Group 3 was compared against Group 2; Group 4 was compared

against Group 2; and Group 5 was compared against Group 2. As indicated by

“**,” the last comparison was the only group to separate from the control (Group

2). The differences between the first two comparisons were not statistically

significantly different. This makes sense because of the experimental design:

individual doses of aripiprazole and lithium were administered that were not

supposed to be effective, i.e., were not supposed to suppress locomotion. Ex. 1076

at 1208, see also 1265-66. Only when used in combination did they display a

positive effect by suppressing the methamphetamine-induced locomotion.

Analogous comparisons were done in the olanzapine arm: Group 8 was

compared to Group 7; Group 9 was compared to Group 7; and Group 10 was

compared to Group 7. None of those groups showed a difference from the control

(Group 7) that was statistically significant.

The Examiner considered the Hirose data and initially raised several

questions. Id. at 1184-85. Contrary to Petitioner’s assertions, Applicant responded

to each of those points. Id. at 1207-08. In a subsequent Office Action, the

Examiner asked additional questions about the data. Id. at 1229-30. In a final

response, Applicant again addressed each of the Examiner’s concerns. Id. at 1265-

67, 1269-70. Based on the experimental paradigm and statistical analysis used,

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Applicant ultimately asserted that “at the very least [the declaration] provides the

Office with a barometer of the combination of aripiprazole + lithium and

olanzapine + lithium in the same environment, whereas Kowatch cannot nor even

tries to do so.” Id. at 1270. After considering Applicant’s arguments and

participating in an interview, the Examiner allowed the claims based on both

Applicant’s arguments and the data. Id. at 1296.

2. The Results Do Not Change by Expressing Them as % Suppression or by Normalizing Them

Dr. Au criticizes Applicant for conducting its analysis on the raw locomotor

count values instead of expressing the results as a % suppression value. Ex. 1004

¶¶ 65-67, Appendix C. While a % suppression value may lead to a simpler

presentation of the data, it is a mathematical fact that the statistical analysis will

come out the same way whether raw data or % suppression values are used.

Dr. Au also asserts that Applicant should have normalized the effects of the

tested drugs against the methamphetamine baseline, again suggesting that by not

doing so, the results would have come out differently. Id. But even Dr. Au’s own

analysis—which is not the one Applicant did or was required to do by the

Examiner—demonstrates that the statistical analysis is the same regardless of

whether raw data (i.e., “uncorrected counts”) or normalized data (i.e., “corrected

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Net-counts”) are used. Ex. 1004 at Appendix C, Tables B & C (p-value is 0.45 for

both the uncorrected, col. 5, and corrected counts, col. 6).

3. The Data was Sufficiently Explained

Dr. Au also contends that the apparent differences between the two

methamphetamine control groups and the intra-group variability affects the quality

of the data. Pet. at 44-45; Ex. 1004 ¶¶ 69-72. But she does not explain why this

“calls into question the reliability of the Hirose Data and its conclusions.” Ex.

1004 ¶¶ 71-72. Instead, she asserts incorrectly that the Examiner raised the issue,

but Applicants did not address it. Ex. 1004 ¶ 71. Dr. Au cites the wrong Office

Action. Id. (citing Ex. 1076 at 1185). The citation should have referred to Ex.

1076 at 1229-30. And Applicant did address that point. Ex. 1076 at 1266.

Applicant noted that the testing involved an in vivo assay in an animal model as

opposed to an in vitro test. Id. Thus, the range of precision and accuracy depends

on numerous factors.

Dr. Au, like the Examiner, also questioned the data in the lithium groups (4

and 9). Ex. 1004 ¶¶ 73-79; Ex. 1076 at 1230. Applicant again addressed the

Examiner’s comments on the record. Ex. 1076 at 1266. Specifically, Applicant

noted that the range generated from the mean ± S.E.M. overlapped between the

two control groups (4 and 9 in table above), which means that any difference is not

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statistically significant.5, 6 Id. Dr. Au argues that Applicant’s data seems to be

contrary to “what is known and expected in the field” for lithium’s affects in the

methamphetamine mouse model. Ex. 1004 ¶ 76. What Dr. Au overlooks,

however, is that Dr. Hirose’s experimental paradigm used sub-therapeutic doses of

5 Dr. Au also quibbles with Applicant’s definition of “range,” asserting—without

citation—that “range” is “normally” understood to represent the difference

between the highest and lowest of all of the observed values. Ex. 1004 ¶¶ 84-85.

Instead, Applicant clearly defined “range” to represent the mean value plus one

S.E.M. Ex. 1076 at 1264-65. Dr. Au readily understood this definition upon

considering the Table and Applicant’s comments. Ex. 1004 ¶ 53 (citing Ex. 1076

at 1264-65).

6 Petitioner and Dr. Au assert that Applicant has defined statistical significance

depending on whether the range of mean ± S.E.M. overlaps or not. Pet. at 47; Ex.

1004 ¶¶ 103-04. Applicant did not define statistical significance that way.

Although it is true that an overlapping range means that there is no statistical

significance between the two groups, the converse, i.e., ranges that do not overlap,

is not automatically statistically significant. Applicant did not argue that. Instead,

Dr. Hirose applied Dunnett’s test, and the only group to show statistical

significance was Group 5 compared to Group 2. Ex. 1076 at 1162-63.

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lithium chloride. Ex. 1076 at 1208, see also 1265-66. In other words, Groups 4

and 9 were not supposed to demonstrate a difference from the methamphetamine

control Groups 2 and 7.

The literature that Dr. Au uses in support of her position is consistent. For

the Hirose data, one dose of 25 mg/kg of lithium chloride was administered 20

minutes before the start of the measurement. Ex. 1076 at 1161. In contrast, the

doses of lithium chloride that exhibited locomotor suppression effect in the

documents cited by Dr. Au were either higher or were administered for longer

periods of time. See Ex. 1004 at Appendix D; Exs. 1036, 1037, 1050, 1038, 1051,

1039, and 1052. For example, in Ex. 1036, mice were administered 22 mg/kg, 67

mg/kg, and 200 mg/kg for 21 days. Ex. 1036 at 2. Only at 67 mg/kg and 200

mg/kg was suppression observed. Id. at 3. The 22 mg/kg dose did not result in a

significant effect at the earlier time points. Id.; see also Exs. 1037 (not a

methamphetamine model; also administered chlordiazepoxide), 1050 (170 mg/kg),

1038 (significant for 25 mg/kg only after 60 mins.), 1051 (pretreatment for 14 days

with 47.5 mg/kg twice a day), 1039 (10-300 mg/kg; no separation from placebo

with lowest dose), and 1052 (47.5 mg/kg). Thus, Dr. Au’s arguments are

irrelevant when one considers the experimental conditions that were used and

clearly explained to the Examiner. Ex. 1076 at 1208, 1265-66.

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4. Dr. Au’s Synergy Model Would Not Have Been Appropriate

Dr. Au asserts that the Hirose experiments were not designed to establish

synergy, and that Applicant should have used the Loewe Additivity model. Pet. at

47-48; Ex. 1004 ¶¶ 93-101, Appendix A. That model, however, “assumes that

drugs in combination are merely different dilutions of the same agent and that an

agent cannot interact with itself.” Ex. 1004 at Appendix A ¶ 13. Stated

differently, this model assumes that lithium and either aripiprazole or olanzapine

have the same mechanisms of action. There is no evidence they do. Indeed,

Tohen speculates that olanzapine may have “unique effects” or mood stabilizing

properties. Ex. 1006 at 7-8. Thus, Dr. Au’s criticisms of Dr. Hirose’s

experimental design are unfounded.

5. Dr. Au’s Arguments Strongly Suggest that a Person of Ordinary Skill in the Art Would Not Have Had a Reasonable Expectation of Success

According to Dr. Au, to establish synergy, one must first establish the

additive effect of the drugs and then compare that with the experimentally

combined effect. Ex. 1004 ¶ 90. To even begin generating those results, however,

she asserts that one would need to understand the dose response curves for all of

the active ingredients—alone and together. Id. at ¶ 91, Appendix A ¶¶ 17-19, 21,

22. She states “[t]o be clear, determination of the nature of drug interactivity

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requires the concentration-effect of dose response curves of single agents and their

combinations obtained at multiple concentration or dose levels.” Ex. 1004 at

Appendix A ¶ 22. She also indicates that the experiments would need to account

for different drug effects at different time points. Id. at ¶¶ 94-96.

Petitioner has not established that any of the data it asserts is required data

was known. Petitioner has not shown that there was a clearly defined dose-

response curve for lithium alone, olanzapine alone, aripiprazole alone, or any of

the agents together. Nor has Petitioner established that lithium and the atypical

antipsychotics have the same mechanism of action. In fact, Tohen clarifies only

that olanzapine may have mood stabilizing properties. Ex. 1006 at 8. And

Petitioner has provided no evidence that olanzapine and aripiprazole are

interchangeable. Supra § III.A.2. Dr. Au asserts that “drug interactivity is highly

complex and the nature of the interactivity can vary from synergy to antagonism

depending on the effect level and drug concentration” (Ex. 1004 at Appendix A ¶

20), i.e., it is highly unpredictable. The Examiner agreed. Ex. 1076 at 1026 (“It is

generally recognized in the art that biological compounds often react unpredictably

under different circumstances”). Thus, Petitioner’s own evidence establishes that a

person of ordinary skill in the art would have had little to no expectation of success

regarding the therapeutic benefit of lithium and aripiprazole in patients

nonresponsive to the mood stabilizers of the claims. Absent a reasonable

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expectation of success, which neither the Office then nor Petitioner now has

established, the submission of any data was unnecessary. And given the paucity of

dose-response data in the art, Applicant’s data in the Hirose declaration

appropriately served as a “barometer” to assist the Examiner. Id. at 1270.

For all of the foregoing reasons, the Board should exercise its discretion

under § 325(d) to deny institution.

V. Petitioner’s Six Grounds of Unpatentability Are Redundant of One Another

“[M]ultiple grounds, which are presented in a redundant manner by a

petitioner who makes no meaningful distinction between them, are contrary to the

regulatory and statutory mandates, and therefore are not all entitled to

consideration.” Liberty Mutual Ins. Co. v. Progressive Casualty Ins. Co.,

CBM2012-00003, Paper 7 at 3 (P.T.A.B. Oct. 25, 2012). Here, Petitioner

introduces its grounds “as independent and not redundant” (Pet. at 24), yet it does

not even attempt to make a meaningful distinction among them. Instead, the

Petition suffers from both horizontal and vertical redundancy.

A. All Grounds Are Horizontally Redundant

Horizontal redundancy occurs when a petition (1) relies on allegedly distinct

documents to “provide essentially the same teaching to meet the same claim

limitation” and (2) fails to “explain why one reference more closely satisfies the

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claim limitation at issue in some respects than another reference, and vice versa.”

Id. Here, all of the proposed grounds rely on “Keck (Ex. 1007) or BMS/Otsuka

Press Release (Ex. 1028)” (Grounds 1-4 and 6) or Citrome (Ex. 1008) (Ground 5)

for an alleged disclosure of aripiprazole. The grounds then pair those documents—

without meaningful distinction—with either APA Practice Guidelines (Ex. 1009),

Tohen (Ex. 1006), Expert Consensus (Ex. 1026), or a combination thereof as

allegedly providing the same teaching: an antipsychotic combined with a mood

stabilizer.

As the Board has explained,

[t]he proper focus of a redundancy designation is not whether the applied prior art disclosures have differences, for it is rarely the case that disclosures of different prior art references will be literally identical. Rather, the focus is on whether the petitioner articulated a meaningful distinction in terms of relative strengths and weaknesses with respect to application of the prior art disclosures to one or more claim limitations.

EMC Corp. v. PersonalWeb Techs., LLC, IPR2013-00082, Paper 33 at 3-4

(P.T.A.B. June 5, 2013) (emphasis added). Petitioner makes no attempt to justify

its repetitive and burdensome grounds by articulating why each ground has

strength and weakness relative to the others. APA Practice Guidelines, Tohen, and

Expert Consensus are factually redundant (and deficient). APA Practice

Guidelines and Tohen report the same preliminary finding that olanzapine in

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combination with lithium or valproate may provide additional efficacy compared

to monotherapy. Ex. 1009 at 31, under “Combination therapy”; Ex. 1006 at 7,

right col., bottom para. And while Petitioner relies on Expert Consensus as an

alternative to those two documents, Expert Consensus does not mention the

preliminary data involving olanzapine or data on any atypical antipsychotic used in

combination with a mood stabilizer. Petitioner provides no basis for subjecting the

Board and Patent Owner to its horizontally redundant grounds.

B. Grounds 1 and 4, Grounds 2 and 4, and Grounds 2 and 6 Are Vertically Redundant

“Vertical redundancy exists when there is assertion of an additional prior art

reference to support another ground of unpatentability when a base ground already

has been asserted against the same claim without the additional reference and the

Petitioner does not explain what are the relative strength and weakness of each

ground.” Liberty Mutual, CBM2012-00003, Paper 7 at 13. Under these

circumstances, “[t]o move forward with such a multiplicity of grounds, Petitioner

must articulate a reasonable basis to believe that from a certain perspective the

base ground is stronger, and that from another perspective the ground with

additional reference is stronger.” Id.

Here, each of Grounds 1 and 2 is vertically redundant of Ground 4. In one

instance, Ground 4 adds Tohen (Ex. 1006) to the identical combination of

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documents asserted in Ground 1. In the second instance, Ground 4 adds APA

Practice Guidelines (Ex. 1009) to the identical combination of documents asserted

in Ground 2. Similarly, in Ground 6, the Petition adds Citrome (Ex. 1008) to the

identical combination of documents asserted in Ground 2. In each occurrence,

Petitioner does not argue that the base ground has anything not found in the ground

that follows. In fact, the later grounds (4 and 6) repeatedly use the phrase “[a]s

discussed above” indicating that Petitioner is merely repeating the same discussion

from the base grounds. Pet. at 34, 35, 39, 40. Accordingly, because Petitioner

fails to articulate anything distinct for Grounds 1 and 2 over Grounds 4 and 6,

Grounds 1 and 2 should be denied.

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VI. Conclusion

For these reasons, Petitioner has not shown that it is reasonably likely to

succeed on its challenge to claims 2, 6, 7, and 9 of the ’939 patent. The Board

should therefore deny the Petition and not institute inter partes review.

Dated: February 28, 2017 By: /Erin M. Sommers/ Erin M. Sommers, Reg. No. 60,974 James B. Monroe, Reg. No. 33,971 Christopher L. McDavid, Reg. No. 70,809 FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P. 901 New York Avenue, NW Washington, DC 20001-4413 Telephone: 202-408-4000; Facsimile: 202-408-4400 Counsel for Patent Owner Otsuka Pharmaceutical Co., Ltd.

U.S. Patent No. 9,125,939 IPR2017-00287

CERTIFICATE OF COMPLIANCE

The undersigned certifies that a copy of the foregoing Patent Owner’s

Preliminary Response contains 13,831 words, excluding those portions identified

in 37 C.F.R. § 42.24(a), as measured by the word-processing system used to

prepare this paper.

Dated: February 28, 2017 By: /Erin M. Sommers/ Erin M. Sommers, Reg. No. 60,974

U.S. Patent No. 9,125,939 IPR2017-00287

CERTIFICATE OF SERVICE

The undersigned certifies that a copy of the foregoing Patent Owner’s

Preliminary Response and Exhibits 2001-2008 were served electronically via

email on February 28, 2017, in their entirety, on the following:

Theresa C. Kavanaugh Nicholas K. Mitrokostas GOODWIN PROCTER LLP 100 Northern Avenue Boston, MA 02210 tkavanaugh@goodwinlaw.com nmitrokostas@goodwinlaw.com Carolyn S. Elmore ELMORE PATENT LAW GROUP, P.C. 484 Groton Road Westford, MA 01886 celmore@elmorepatents.com

Petitioner has agreed to electronic service. Dated: February 28, 2017 By: /Erin M. Sommers/

Erin M. Sommers, Reg. No. 60,974